Plague is caused by infection with the bacterium Yersinia pestis, a category A bioterrorism agent. Any strategy to protect against Y. pestis must recognize that the pneumonic form of the disease develops within days, and thus anti-Y. pestis protection has to be functional within days following an attack. This proposal presents a strategy for both rapid and long lasting protection against Y. pestis based on our experience in using adenovirus (Ad) gene transfer vectors to develop anti-bacterial vaccines, and the ability of Ad vectors to code for single chain antibodies against specific antigens. The underlying concept is that Ad-based gene transfer vectors can be used to evoke systemic, robust acquired immunity, as well as rapid passive immunity against Y. pestis antigens, and that both forms of protection can be achieved with a single administration of a single vector. The proposal uses an in vivo gene transfer-based strategy with a single Ad vector to simultaneously evoke rapid humoral immunity against Y. pestis (via an anti-Y. pestis single chain antibody coded by the vector), while also functioning as a vaccine to evoke endogenous host responses against Y. pestis antigens (via Y. pestis antigens coded by the vector). The 3 specific aims outline studies to achieve these goals by developing the vaccine and single chain antibody strategies independently, and then combined. Aim 1. To evaluate the hypothesis that a vaccine based on a replication deficient Ad vector encoding the Y. pestis V and F1 antigens will evoke robust systemic humoral immunity against these antigens and protect against challenge with Y. pestis. Aim 2. To assess the hypothesis that an Ad vector encoding a single chain antibody against an epitope of Y. pestis V or F1 antigen will provide robust, rapid humoral immunity against these antigens and protect against challenge with Y. pestis. Aim 3. To examine the hypothesis that a combined passive and active anti-Y. pestis protection can be achieved with a single administration of a single Ad vector expressing anti-Y. pestis single chain antibody and Y. pestis antigens.